We demonstrate immunological effects of PCSK9 in relation to activation and maturation of DCs and plaque T cells by OxLDL, a central player in atherosclerosis. This may directly influence atherosclerosis and cardiovascular disease, independent of LDL lowering.

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Background:LDL-levels are increased by Proprotein convertase subtilisin kexin 9 (PCSK9) which targets the LDL-receptor (LDLR). We reported that PCSK9 has immune modulatory properties in addition to LDL-lowering and ameliorates dendritic cell (DC) activation by oxidized LDL (OxLDL)1, which is abundant in atherosclerotic plaques. OxLDL is also raised and associated with cardiovascular disease (CVD) in SLE.1-3Objectives:We here investigate the role of PCSK9 in SLE both in a clinical context and in experimental ex vivo studies. The objective is to investigate if PCSK9 and its inhibition could be of relevance in SLE in addition to LDL-level related propertiesMethods:PCSK9-levels were determined by ELISA among SLE patients (n=109) and age- and sex-matched population-based controls (n=91). Common carotid intima-media thickness (IMT) and plaque occurrence were determined by B-mode ultrasound. Plaques were graded by echogenicity. Human peripheral blood monocytes from SLE patients or controls were differentiated into DCs. Effects of PCSK9 and its inhibition by silencing were studied.Results:PCSK9-levels were non-significantly higher among SLE-patients as compared to controls but associated significantly with SLE disease activity, as determined by SLAM (0.020) or SLEDAI (0.0178). There was no association between PCSK9-levels and atherosclerosis as determined by IMT, prevalence of plaques or echolucent (potentially vulnerable) plaques. PCSK9 levels were significantly associated with CVD among SLE-patients but not after adjustment for age.OxLDL induced PCSK9 in DCs and DC-maturation with increased expression of CD86 and HLA-DR. The effects were significantly stronger in DC from SLE patients than from controls. Silencing of PCSK9 abolished OxLDL-induced DC-maturation.Conclusion:PCSK9 is associated with disease activity in SLE. One underlying cause could be OxLDL, promoting DC-activation which depends on PCSK9. OxLDL induces PCSK9, an effect which is higher among SLE-patients.PCSK9 could play an unexpected immunological role in SLE and inhibition of PCSK9 could potentially play a role in disease amelioration, pending on clinical studies.References:[1]Liu A and Frostegard J. PCSK9 plays a novel immunological role in oxidized LDL-induced dendritic cell maturation and activation of T cells from human blood and atherosclerotic plaque.J Intern Med. 2018.[2]Frostegard J, Svenungsson E, Wu R, Gunnarsson I, Lundberg IE, Klareskog L, Horkko S and Witztum JL. Lipid peroxidation is enhanced in patients with systemic lupus erythematosus and is associated with arterial and renal disease manifestations.Arthritis Rheum. 2005;52:192-200.[3]Frostegard J. Immunity, atherosclerosis and cardiovascular disease.BMC Med. 2013;11:117.Disclosure of Interests:Anquan Liu: None declared, Mizanur Rahman: None declared, Ingiäld Hafström: None declared, Sofia Ajeganova: None declared, Johan Frostegård Grant/research support from: Unconditional competitive grant from Amgen, related only to PCSK9, not the topic of this abstract